This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [16,18,32]) are generated by the genes CALCR (which codes for the CT receptor, CTR) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CTR; these in turn produce variants of AMY receptors [32], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin (CALCA, P01258), α-CGRP (CALCA, P06881) (formerly known as CGRP-I), β-CGRP (CALCB, P10092) (formerly known as CGRP-II), amylin (IAPP, P10997) (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin (ADM, P35318) and adrenomedullin 2/intermedin (ADM2, Q7Z4H4). There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [20]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the "gepant" class of CGRP receptor antagonists. There are also species differences in agonist pharmacology; for example, CGRP displays potent activity at multiple rat and mouse receptors [4,10]. The summary table only reflects human receptor pharmacology.

It is important to note that a complication with the interpretation of pharmacological studies with AMY receptors in transfected cells is that most of this work has likely used a mixed population of receptors, encompassing RAMP-coupled CTR as well as CTR alone. This means that although in binding assays human calcitonin (CALCA, P01258) has low affinity for ¹²⁵I-AMY binding sites, cells transfected with CTR and RAMPs can display potent CT functional responses. Transfection of human CTR with any RAMP can generate receptors with a high affinity for both salmon CT and AMY and varying affinity for different antagonists [5,14-15]. The major human CTR splice variant (hCT_(a), which does not contain an insert) with RAMP1 (i.e. the AMY_1(a) receptor) has a high affinity for CGRP [37], unlike hCT_(a)-RAMP3 (i.e. AMY_3(a) receptor) [5,14]. However, the AMY receptor phenotype is RAMP-type, splice variant and cell-line-dependent [28,33,36]. Emerging data suggests that AMY₁ could be a second CGRP receptor [34].

The ligands described have limited selectivity. Adrenomedullin has appreciable affinity for CGRP receptors. CGRP can show significant cross-reactivity at AMY receptors and AM₂ receptors. Adrenomedullin 2/intermedin also has high affinity for the AM₂ receptor [16]. CGRP-(8-37) acts as an antagonist of CGRP (pK_i ~8) and inhibits some AM and AMY responses (pK_i ~6-7). It is weak at CT receptors. Human AM-(22-52) has some selectivity towards AM receptors, but with modest potency (pK_i ~7), limiting its use [17]. Olcegepant (also known as BIBN4096BS, pK_i~10.5) and telcagepant (also known as MK0974, pK_i~9) are examples of the "gepant" class of small molecule antagonists. These are selective for the CGRP receptor over the AM receptors but depending on the compound, have variable affinity for the AMY₁ receptor [11]. These antagonists tend to have higher affinity at primate receptors, compared to rodent receptors [27,37].

G_s is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca²⁺, ERK, Akt), and G proteins can be activated [34]. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL (P04424) is important for the coupling of CLR to adenylyl cyclase [8].

[¹²⁵I]-Salmon CT is the most common radioligand for CTR but it has high affinity for AMY receptors and is also poorly reversible.

* Key recommended reading is highlighted with an asterisk

Booe JM, Walker CS, Barwell J, Kuteyi G, Simms J, Jamaluddin MA, Warner ML, Bill RM, Harris PW, Brimble MA et al.. (2015) Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor. Mol Cell, 58 (6): 1040-52. [PMID:25982113]

* Hay DL, Garelja ML, Poyner DR, Walker CS. (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol, 175 (1): 3-17. [PMID:29059473]

Hay DL, Pioszak AA. (2016) Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu Rev Pharmacol Toxicol, 56: 469-87. [PMID:26514202]

* Kato J, Kitamura K. (2015) Bench-to-bedside pharmacology of adrenomedullin. Eur J Pharmacol, 764: 140-8. [PMID:26144371]

* Kotliar IB, Lorenzen E, Schwenk JM, Hay DL, Sakmar TP. (2023) Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins. Pharmacol Rev, 75 (1): 1-34. [PMID:36757898]

* Russell FA, King R, Smillie SJ, Kodji X, Brain SD. (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev, 94 (4): 1099-142. [PMID:25287861]

Russo AF. (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol, 55: 533-52. [PMID:25340934]

* Russo AF, Hay DL. (2023) CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiol Rev, 103 (2): 1565-1644. [PMID:36454715]

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Subcommittee members: Debbie Hay (Chairperson) Department of Pharmacology and Toxicology School of Biomedical Sciences Division of Health Sciences University of Otago Dunedin 9054 New Zealand Christopher S. Walker School of Biological Sciences Thomas Building 3A Symonds Street University of Auckland Private bag 92019 Auckland 1142 New Zealand

Other contributors: Michael L. Garelja Department of Pharmacology and Toxicology School of Biomedical Sciences Division of Health Sciences University of Otago Dunedin 9054 New Zealand